As soldiers are returning from wars around the globe, traumatic brain injury (TBI) has been reported among veterans. Brain structural damage of different degrees and functional/behavioral deficits such as post-traumatic stress disorder (PTSD) including post-TBI depression (PTD) are frequently seen among these patients. So far, there is basically no effective treatment for acute TBI or chronic patients. In recent years, cell-based therapy provides an attractive and coherent approach in regenerative medicine. Based on the latest advancement and our preliminary data, we propose a novel delayed treatment by directly converting endogenous astrocytes accumulated around the injury site into induced neurons (iNs) in the chronic phase after TBI. In a mild/moderate TBI mouse model, the direct reprogramming gene NeuroD1 (ND1) that targets reactive astrocytes will be expressed in the peri-contusion region by lentiviral injection. We hypothesize that the intra-lineage direct reprogramming provides a viable endogenous source of new neurons by leveraging existing proliferative astrocytes after TBI and helps to prevent the development of PTD (Specific Aim 1). We propose that the reprogramming gene expression will effectively reduce gliosis or glial scar formation during the chronic phase after TBI, which will lessen physical and chemical barriers for regeneration and significantly facilitate axonal outgrowth and other regenerative activities (Aim 2). It is further hypothesized that combined rehabilitation of treadmill exercise will improve ND1-induced gene regulation, post-TBI tissue repair and functional activities (Aim 3). We propose that, in the combination therapy, iNs arisen within the host tissue enriched by up-regulated genes such as BDNF and oxytocin are conducive to integration with existing neural networks. Our preliminary data demonstrate the feasibility of converting astrocytes into mature neurons, increased regenerative/behavioral genes, and improved psychological behaviors chronically after TBI. The goal of this investigation is to demonstrate and develop an effective treatment for veteran patients with TBI-related PTD.